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89Sampling and Testing Plan
SAMPLING AND TESTING PLAN TO PERFORM
ACCEPTABLE QUALITY LIMIT
AQL (Acceptable Quality Limit) Sampling is a method widely used to dene a pro-
duction order sample to nd whether or not the entire product order has met the cli-
ent’s specications. Based on the sampling data, the customer can make an informed
decision to accept or reject the lot. There are various sampling plans such as single
sample plan or multiple sampling plans for performing AQL.
AQL sampling is performed to identify and accept numbers of defective units (i.e.
critical, major, and minor defects) in a lot or a batch.
•
AQL sampling can be performed at stages such as but not limited to after
compression, during online compression, after coating, after lling of cap-
sules, during the online lling of capsules.
• Samples shall be withdrawn as per AQL chart.
•
During online processing of a batch, sample size at a particular frequency
can be calculated as per the below mentioned formula:
=×n
N
R
F
Where, n
= sample size at each interval
N = Total No. of samples
R
= Total run time of machine in minutes
F = Frequency or time interval in minutes
•
Sampling can also be performed after processing of a batch by dividing
the total sample size with the total nos. of containers containing the batch.
Sampling shall be performed by taking equal nos. of samples from indi-
vidual containers randomly.
CONCLUSION
Sampling performed in various stages of solid oral dosage formulation manufactur-
ing industries plays a critical role in lot or batch acceptance investigation in case of
any deviation or incidence which in turn helps to maintain or improve or develop the
quality of a product according to regulatory or in house requirements of a pharma-
ceutical industry in view of patient safety.
Sampling methods other than those mentioned above can be adopted hav-
ing sound scientic justication and rationale. There may be many more sam-
pling errors associated with sampling other than those mentioned in the article.
Sampling errors should be identied and can be avoided by regular training and
monitoring of samplers and/or by performing sampler validation in sampling
activities.
Sampling and testing plans for every stage of the process for a liquid dosage form
are dened in the chart below.
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90 Basics of Pharmaceutical Manufacturing and Quality Operations
SAMPLING AND TESING PLAN FOR PRODUCT ABC
LOT: W/O DATE: RU N No.
In‑Process
Sample No. Nature of Sample Location/Time Responsibility Test to Be Preformed Sampled By Time/Date of Sample
In
-Process Sample Port (100 mL) Validation IP (Write the tests to be performed
for all respective areas)
In-Process Sample Port (100 mL) Validation IP
Bulk Hold (When required) Sample Port–Time 0 Validation FP
Sample Port–Time 24
hours Validation FP
Condensate Purge
Sample No. Nature of Sample Location/Time Responsibility Test to Be Preformed Sampled By Time/Date of Sample
Condensate Purge XX L (100 mL) Validation Test Active
XX L (100 mL) Validation Test Active
(Continue as required) XX L (100 mL) Validation Test Active
Batch Homogeneity
Sample No. Nature of Sample Location/Time Responibility Test to Be Preformed Sampled By Time/Date of Sample
Batch Homogeneity Beginning of Fill
(XX bottles)
PKG/Validation Test Active
Beginning of Filling
(XX bottles)
PKG/Validation Test Active
Middle of Filling
(XX bottles)
PKG/Validation Test Active
Middle of Filling
(XX bottles)
PKG/Validation Test Active
End of Filling
(XX bottles)
PKG/Validation Test Active
End of Filling
(XX bottles)
PKG/Validation Test Active
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91Sampling and Testing Plan
QUESTIONS AND ANSWERS
1. Why a sampling Plan in validation is important?
Answer: In the process validation, sampling and testing plans must be
developed to consider the specic attributes being measured and the risks
associated with accepting a defective lot.
2. Dene a sample
Answer: A sample is a portion of a material collected according to a dened
sampling procedure.
3. What are the signicant aspects of a sampling procedure?
Answer: The sampling procedures documented in the protocol should
provide;
a. Sample locations, sample size, and sample frequency and should also
include the tests or assessments required.
b. Must be representative of the population.
c. Should be designed in a way so that any segregation during blending and
mixing, transport, or handling could be determined.
d. Should also be able to assess any variability or other factors that might
impact production consistency.
4. How many sampling locations are recommended from a blender to
assess the blend uniformity?
Answer: It is generally considered that a blend uniformity sampling from
tumble blending should be carried out from, at least ten locations in the
blender.
Whereas for ribbon blending, a minimum of 20locations in the blender
should be sampled and chosen to adequately address probable dead spots
especially in the corners and discharge areas.
5. What should be the logical approach in choosing the Beginning, Middle,
and End samples during a lling process?
Answer: During the lling process, the following rules should be consid-
ered at minimum for lling/packaging sampling to establish the Beginning,
Middle, and End samples:
• Beginning of Filling: Logically the rst ten samples should be collected
and tested as “Beginning samples”.
• Middle: During the entire lling process, samples should be collected
at a frequency established in the protocol as per the process run and
then ten samples collected from the entire pool to create the “Middle
samples”.
•
End: Like the rst ten packages, the last ten packages just before the end
of lling should be collected as the “End samples”.
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92 Basics of Pharmaceutical Manufacturing and Quality Operations
6. What other changes in a process may trigger a re‑validation and conse‑
quently change in sampling plan would be required.
Answer: The following changes may trigger a re-validation and a changed
sampling plan;
a. A change in the supplier or manufacturer of a raw material is critical
and must be assessed for the impact on product’s quality. Based on the
assessment, decision is made if the change (made to an active or excipi-
ent in a formulation) requires revalidation. The sampling requirement
for the revalidation will be based on risk and documented in the Raw
Material Evaluation Report.
b. A similar strategy, as mentioned above, needs to be carried out in the
case of a change in the process and/or equipment. Each process or equip-
ment change should be addressed individually and the sampling and
testing should be based on risk.
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7. 3
Process Validation
Report Writing
The process validation report is a document which demonstrates evidence that
a manufacturing process is capable of consistently delivering quality products. It
provides a proper documentation of process validation protocols. Process valida-
tion reports are generally completed before the routine commercial production for a
new product. The validation report may clarify if the batches discussed in the report
are going to be used for commercial purpose or not. Pharmaceutical manufacturing
industries typically use a process validation report template to ensure compliance
with US Food and Drug Administration (FDA) requirements.
The validation report should contain an executive summary listing the most prom-
inent results of the validation. A short introduction stating who produced it, when,
and for what purpose. The process validation report generally includes the details of
the materials used with the batch numbers, the equipment with the ID numbers, and
the personnel who carried out the processes with their training records ensuring that
the process controls were performed by experienced operators.
The raw data is further discussed in the report and if there has been any anomaly
during the validation study, it is addressed in the report with the investigation details as
well as the outcome of the investigation and corrective and preventative actions taken.
In the following pages, a validation report is being given step by step to clarify
how a process validation report is written.
OBJECTIVE
The objective of the report is to document the process results and process parameters
obtained during the manufacture of [enter blend/granulate name and batch number]
and [enter Capsule/Tablet product name and batch number] in the Manufacturing
facility at [enter site name].
The [enter blend/granulate name and batch number] are the [rst/second/third]
validation blend in this study manufactured for the Local market. The [enter Capsule/
Tablet product name and batch number] are the [rst/second/third] run of three vali-
dation batches to be manufactured for the [Local /export] markets. Refer to table 1.0
below for details on all the validation runs covered in this report and from previous
interim reports.
VALIDATION STRATEGY
The manufacturing process of the xyz blend name (commercial lot size Y kg) and
[enter product caps/tab] (enter batch size or commercial batch size may depend
93
DOI: 10.1201/9781003366393-10
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94 Basics of Pharmaceutical Manufacturing and Quality Operations
on market demand) were validated under the control of the Technical Services
Department. [Enter for both export and Local if applicable].
A [concurrent/prospective/retrospective] validation approach was used for this
validation study.
Justify concurrent e.g., because some of the [enter product name] dosages are not
manufactured very frequently in the Manufacturing facility at [enter site name].
All validation batches were manufactured following the same manufacturing pro-
cess as detailed in the manufacturing instructions [give Manufacturing Instruction
number and current versus protocol version number/date].
All critical process variables in the manufacturing process [blending/granulation
and Tableting /encapsulation] were reviewed. [These/this] validation [batch/es] were
analyzed as set out in [enter section reference] of the protocol [enter protocol number]
and the results are summarized in [enter Section reference] of this report.
This report will document the number of blend / granulate samples from the run,
e.g., minimum of ten locations from the blender to show blend uniformity/homogene-
ity [dead spot] characterization in modied processes only, reference [enter no] and
Blend sampling strategy report [enter no]. NIR blend analysis will be run on all blend
samples to assess blend uniformity.
REPORT APPROVALS SHEET
PRODUCT NAME:
CODE:
BATCH NUMBER:
PRODUCTION STAGE:
Table of Content
Sr.No. Description Page No.
REPORT APROVALS SHEET 1
EXECUTIVE SUMMARY 4
INTRODUCTION 5
TYPE OF VALIDATION 5
VALIDATION STRATEGY 6
DOCUMENTATION 7
CRITICAL PROCESS PARAMETERS (MANUFACTURING) 8
Formulation 8
Equipment used 9
Manufacturing process 10
Process ow, variables and responses 10
Addition and mixing 11
Addition of Iron oxide red, etc. 11
(Continued
)
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95Process Validation Report Writing
2 EXECUTIVE SUMMARY
This process validation report has the compilation of data, including manufacturing
process variables, packaging variables, and analytical results for the product xyz
1 mg Tablets which was successfully manufactured at the plant ABC Pharmaceutical
industries.
Three consecutive validation batches were manufactured of xyz 1 mg Tablets
and the complete batch document were reviewed, and related documents like Batch
Manufacturing formula, Batch Packaging record, QC analytical methods, and related
SOPs were checked.
In order to achieve the goal of process validation the analytical data of three
consecutive batches was compiled and statistically evaluated and represented graphi-
cally for the assay of active ingredients.
Table of Content
Sr.No. Description Page No.
Quantity of Granulating Solution 11
Mixing and Sifting of Avicel 101, etc. 11
Mixing and Sifting of API 11
Mixing and Sifting of Iron oxide red, etc. 12
Mixing of all Sifted material 12
Preparation of wet granules 12
Drying of Granules 13
Checking of LOD 13
Grinding of Dry Granules 13
Lubrication 14
Yield Calculation of Granules 14
Compression 14
Uniformity of weight 15–17
CRITICAL PROCESS PARAMETERS (PACKAGING) 18
Blistering defects 18
Final Packaging Record 19
SUMMARY OF QC RESULTS 20
Results data table of API assay 20
Results data table for Impurities 22
Results data table of Microbial Analysis 23
BATCH YEILD 24
RISK ANALYSIS 25
COMPLIANCE TO FINISHED PRODUCT SPECIFICATION 26–27
OBSERVATION 28
CONCLUSION 29
REVALIDATION 30
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96 Basics of Pharmaceutical Manufacturing and Quality Operations
All three batches meet the acceptance criteria for all quality attributes set up in
the nished product specication and related SOPs.
3 INTRODUCTION
3.1 objective of the vaLidation
The aim of this report is to document that the process of production of three consecu-
tive batches of pharmaceutical product xyz 1
mg Tablets is effective in consistency
and reproducibility and meets all predetermined specications and quality attributes
using the actual process to verify at least the following:
• Final Mixing homogeneity
• Physical parameters
• Content of Active ingredient
• Normal operating parameters
• Operating procedures for product manufacturing
The validation report was focused to the critical points for quality assurance of the
production process in the way that:
• Content of active ingredient–assay
• Microbial Analysis
Complying with specication and acceptance criteria established in nished product
specication for xyz 1 mg Tablets.
This report presents the results of the following two consecutive production
batches for xyz 1 mg Tablets.
4 TYPE OF VALIDATION
Prospective validation
Batch No. Batch Size
Theoretical
Units
Produced
Manufacturing
Date
Expiry
Date
001 xx kg 100,000
002 xx kg 100,000
003 xx kg 100,000
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97Process Validation Report Writing
5 VALIDATION STRATEGY
Three consecutive batches of the above-mentioned product were manufactured in the
manufacturing area. These batches were used for the above-mentioned type of pro-
cess validation study. The work was focused on the evaluation of the following steps:
i. Review of the manufacturing formula and method, packaging instructions,
raw material and nished product specications and related SOPs.
ii. Issuance of Raw Materials and Equipment used during manufacturing.
iii. Mixing time and mixer speed at different manufacturing steps.
iv. Temperature of vessel during mixing.
v. The routine in-process control data and the critical parameters according to
the manufacturing formula and method (MFM).
vi. Manufacturing and nal batch yield.
vii. Critical packaging parameters.
viii. Physicals, Chemical, and microbiological properties of the active ingredi-
ents for nished product.
6 DOCUMENTATION
Check the following in use documents before the start of process validation.
Reference No. Issue Date
Manufacturing Formula and Method
(MFM)
Master Packaging Instructions
Finished Product Specication
In-process Specication (Manufacturing)
In-process Specication (Packaging)
Raw Material Specications
1: API (Micronized)
3: Lactose Monohydrate
4: Microcrystalline Cellulose (Avicel)
5: Sodium Starch Glycolate (Primojel)
6: Crospvidone (Kollidon CL)
7: Polysorbate 80 (Tween 80)
8: Iron Oxide Red
9: Iron Oxide Red
10: Magnesium Stereate
11: Puried Water
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98 Basics of Pharmaceutical Manufacturing and Quality Operations
7 CRITICAL PROCESS PARAMETERS (MANUFACTURING)
7.1 forMuLation (active/inactive inGredients)
Composition of Product
Names of raw materials in the table above are given as an example as most of the
solid dosage forms are manufactured using the same raw materials as excipients.
However, the main logic here is to only provide a basic idea to the readers.
7.2 eQuiPMent used
The details of major equipment used during manufacturing and packaging are given
in below table.
The names of the equipment in the table above are the ones generally used in the
manufacture of a solid dosage form product. However, their names are given here
only to provide an idea to the readers.
Scale
mg/tablet Item No. Material’s Name Code
Quantity/Batch
14.0 kg
(100,000 tablet)
QC
Status
1 API (Micronized) Released
4 Lactose Monohydrate Released
3 Microcrystalline Cellulose
(Avicel pH101)
Released
4 Sodium Starch Glycolate
(Primojel)
Released
5 Crospvidone (Kollidon CL) Released
6 Polysorbate 80 (Tween 80) Released
7 Iron Oxide Red Released
8 Magnesium Stearate Released
9 Puried water Released
Sr.No. Equipment Name Manufacturer’s Name Model Serial No.
Sifter
Mixer
Tray Dryer
Dry Granulator
Tablet Press
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